Compounds and process

ABSTRACT

A process for preparing 1 alpha -hydroxylated calciferols is described. Intermediates used in the process are also provided.

This is a division of application Ser. No. 916,921, filed June 19, 1978now U.S. Pat. No. 4,206,131.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention concerns the preparation of 1-hydroxycalciferol (that is1-hydroxy Vitamin D) derivatives with special reference to the1α-hydroxy derivatives. These compounds are well known to be highlyactive in combating many disorders of calcium metabolism.

2. Prior Art

Numerous preparation of 1α- and 1β-hydroxy calciferol derivatives havebeen described. A brief list includes: 1α-hydroxycholecalciferol [DeLucaet al. U.S. Pat. No. 3,741,996; Barton et al. J.A.C.S. 95, 2748 (1973);Furst et al., Helvetica 56, 1708 (1973)]; 1β-cholecalciferol [Mazur etal., J.O.C. 42, 3597 (1977); DeLuca et al., Chem. Comm., 890 (1977)];1α,25-dihydroxy cholecalciferol [DeLuca et al., Tetrahedron Letters,4147 (1972); Barton et al., Chem. Comm. 203 (1974); Uskokovic et al.,U.S. Pat. No. 3,993,675]; 1β,25-dihydroxycholecalciferol [DeLuca et al.,Chem. Comm., 890 (1977)]; 1α-hydroxyergocalciferol [DeLuca et al.,Science 186, 1038 (1974)]; 1α,25-dihydroxyergocalciferol [DeLuca et al.,Biochemistry 14, 1250 (1975)]; 1α,24 R and S-dihydroxycholecalciferols[lkekawa et al., J. C. S. Perkin l, 1421 (1975)]; 1α ,24 R and S,25-trihydroxycholecalciferols [lkekawa et al., Chem. Pharm. Bull., 23,695 (1975)].

This is by no means an exhaustive list but it is representative of themajor approaches to the major 1-hydroxy derivatives of calciferol. Asalient feature of almost all of these syntheses is that the 1α-hydroxycalciferol is derived from its 1α-hydroxy steroidal pro-vitamin isomerthrough the standard photochemical and thermal rearrangements of thissystem.

Two approaches avoid this undesirable photochemical transformation. Oneis that of Lythgoe et al. [J. C. S. Perkin 1, 2654 (1974)] whichdescribed a total synthesis of 1α-hydroxy-cholecalciferol. This is alengthy synthesis and is of academic interest only not being at allsuitable for large scale production, especially for the more highlysubstituted derivatives. The second is that of Pelc who describes thedirect oxidation of cholecalciferol [Steroids 30, 193 (1977)], but theyield of the desired 1α-hydroxy-cholecalciferol is exceedingly low.

SUMMARY OF THE INVENTION

This invention pertains to a chemical process for the conversion of acalciferol derivative into its 1α-hydroxy or 1β-hydroxy-cis or transanalogs. The process comprises (1) converting derivatives of calciferolto selenium analogs. (2) oxidising the selenium analogs, and (3)converting the products of the oxidation to 1α-(or 1β-) hydroxycalciferols. The invention also includes intermediates formed and usedin the process.

DETAILED DESCRIPTION OF THE INVENTION

The novel process, briefly described above, can be illustratedschematically as follows: ##STR1## wherein R₁ is selected from the groupconsisting of hydrogen, trimethylsilyl, t-butyldimethylsilyl,phenyldimethylsilyl, acyl of from 2 to 6 carbon atoms, and aroyl whereinthe aroyl group is benzoyl or substituted benzoyl; R₂ is selected fromthe group consisting of ##STR2## wherein R₃ is selected from the groupconsisting of hydrogen, hydroxy, trimethylsilyloxy, acyloxy of from 2 to6 carbon atoms, inclusive, and aroyloxy, wherein aryl is selected fromthe group consisting of benzoyl and substituted benzoyl; R₄ is selectedfrom the group consisting of hydrogen, hydroxy, trimethylsilyloxy,acyloxy of from 2 to 6 carbon atoms, inclusive and aroyloxy; and whereinR₃ and R₄ when taken together form a group selected from acetonide,group ##STR3## wherein R₅ is selected from the group consisting ofhydrogen, methyl, hydroxyl, and lower alkoxy of from 1 to 5 carbonatoms, inclusive;

and the "selenium reagent" is selected from the group consisting of arylselenenyl halide, ArSeX, wherein Ar is phenyl or phenyl substituted withchloro, bromo, lower alkyl, lower alkoxy or nitro, and X is chlorine,bromine, fluorine or iodine, aryl seleninic anhydride, ##STR4## andAr--Se--R₆ wherein R₆ is selected from the group consisting of ##STR5##and Ar is the same as defined above.

In the foregoing designation of variable, "acyl of from 2 to 6 carbonatoms" means acetyl, propionyl, butyryl, pentynyl and hexenyl, and theisomeric forms thereof.

"Substituted phenyl" means lower alkyl, lower alkoxy, halogen, nitro andcyano substituted phenyl.

"Lower alkyl" means methyl, ethyl, propyl, butyl, pentyl and isomericforms thereof.

"Lower alkoxy" means methoxy, ethoxy, propoxy, butoxy, pentoxy andisomeric forms thereof.

The starting cis- or trans- vitamin D materials, 1a, 1b are commerciallyavailable or can be prepared by methods described in the literature.Step 1 is conducted by reacting a compound of formula 1 with a seleniumreagent having the formula described above, usually in the presence of asolvent. The amount of selenium reagent used should be between 1 and 10moles per mole of Vitamin D compound and the reaction conducted attemperatures ranging from -80° to ±100° C. for periods ranging from afew minutes to several hours, the exact conditions being determinedlargely by the nature of the selenium reagent used.

For example, when the selenium reagent is phenyl selenenyl chloride thereaction is conducted in the range -80° to -50° C., preferably at -68°for a period of only a few minutes with a molar ratio of 1:1. Methylenechloride is the preferred solvent although other halogenatedhydrocarbons, as well as ethers may be used. After the addition of thephenyl selenenyl chloride, a base such as alkali metal alkoxides orpreferably an amine such as triethylamine, diazabicyclononene ordiazabicycloundecene, is added.

When the selenium reagent is an aryl seleninic anhydride, the preferredreagent is phenyl seleninic anhydride. Solvents such as benzene,toluene, halogenated hydrocarbons, alkanes, ethers may be used. Thepreferred solvent is chloroform, and the preferred temperature is at theboiling point. The preferred molar ratio is 1:1.

When the selenium reagent is an N-(arylselenenyl)succinimide thepreferred reagent is N-(phenylselenenyl)succinimide. Solvents such ashalogenated hydrocarbons, for example methylene chloride or chloroform,aromatic hydrocarbons, for example benzene or toluene, ethers such astetrahydrofuran or dioxan may be used. Polar aprotic solvents such asdimethylsulfoxide, dimethylformamide, tetramethylurea orhexamethylphosphoric triamide are preferred. The molar ratio of seleniumreagent to the calciferol derivative may vary from 1 to 10 althoughpreferred is approximately 4. The temperature of the reaction may varyin the range of room temperature to 100° C., the preferred temperaturerange being approximately 70°-75° C.

The selenium compound III can be obtained from the reaction mixture byconventional means such as crystallization, extraction, chromatographyand combinations thereof. The selenium compound III is produced inrelatively small amounts and is not usually isolated pure, but rathercarried on directly to the next stage of the reaction sequence.

In step 2, the next stage of the reaction sequence, compounds II and IIIare reacted, with an oxidizing agent, preferably in presence of asolvent. The preferred mode of conducting the oxidation is to use thepurified III alone. Compound II, being more difficult to isolate thanIII, is usually oxidized as a mixture with III. Suitable oxidizingagents include m-chloroperoxybenzoic acid, peracetic acid and ozone, thepreferred oxidant being hydrogen peroxide. Suitable solvents includemethylene chloride, chloroform, dioxane and the preferred solvent inconjunction with hydrogen peroxide is tetrahydrofuran. The range ofmolar ratio of hydrogen peroxide to the allylic selenide III is 1 to 5,preferred being about 2.5 to 3. The temperature range for conducting theoxidation is from -40° to +45° C., the preferred range being -15° to 0°C. The reaction products IV, V, VI and VII resulting from the oxidationare recovered from the reaction mixture by conventional methods such ascrystallization, extraction, distillation, chromatography andcombinations thereof.

The products of the oxidation are the more desirable 1αa-hydroxyderivatives and the less desirable 1β-hydroxy derivatives. Steps 3 and 4represent methods for converting the 1β-hydroxy-derivatives to the moredesirable 1αa-hydroxy-derivatives by a process of epimerization forexample by means of the Mislow rearrangement sequence [see Evans et al.,Accounts of Chemical Research, 7, 147 (1974)] or by means of the methodof Loibner et al. I, Helvetica, Vol. 59, p. 2100 (1976) and Loibner etal. II, Helvetica, Vol. 60, p. 417 (1977).

The method of converting 1β-hydroxy to the 1α-hydroxy-derivative allowsa higher yield of the desirable 1α-hydroxy-derivative to be obtained, Vthereby being converted to IV and VII to VI.

In step 5 the 1α-hydroxy-trans-vitamin D derivative, VI, is converted tothe desired 1α-hydroxy-cis-vitamin D derivative IV by irradiation. Thisphotochemical transformation of a trans-vitamin D derivative to thecis-vitamin is well known in the art and is based upon the brilliantpioneering studies of Havinga et al., [Rec. Trav. Chim. Pays-Bas 74,1125 (1955)] and of Inhoffen et al. [Berichte 90, 2544 (1957); J. Chem.Soc., 385 (1959)].

It is likewise possible to isomerise a 1β-hydroxy-trans-derivative VIIto the 1β-cis-derivative V as in process 6. V may then be isomerised asmentioned above to IV. However, it is preferable that VII be isomerisedfirst to VI by process 4 and then VI isomerised photochemically byprocess 5 to cis-vitamin IV. In this preferred sequence VII-VI-IV, theyield of IV is optimum. In terms of the separation of IV from VI whichis necessary after the photolysis of VI to IV, an equilibrium mixturebeing obtained, it is preferable that R₂ be such that thechromatographic polarity of the side chain be as low as possible. Thusif hydroxyls were present in the original vitamin in the 24, 25 and/or26-positions, it is preferred that they be protected by a non-polarprotecting group such as trimethylsilyl or acetate. In this way the easeof the chromatographic separation of IV and VI is enhanced.

When preparing compounds of formulas IV thru VII wherein R₂ is either##STR6## and R₅ is hydrogen, it is preferred to conduct the seleniumreaction and the subsequent oxidation reaction on compounds wherein R₅is alkyl or alkoxy and then replace the alkyl or alkoxy group withhydrogen.

In steps 7, 7a, 7b, and 7c the compounds of formulae IV, V, VI and VIIare subjected to hydrolysis to yield the dihydroxy derivatives VIII, IX,X and XI respectively. The hydrolysis is accomplished by utilizingmethods and reagents well known in the art. The particular reagent usedwill depend upon such things as the nature of the radical R₁. Forexample cold dilute hydrochloric acid can be used when R₁ istrimethylsilyl, and aqueous methanolic potassium hydroxide can be usedwhen R₁ is benzoyl. Selection of the appropriate reagents for hydrolysiswill be obvious to those skilled in the art. Although the processes 7a,7b and 7c are easily carried out, and the compounds IX, X and XI therebyeasily obtained it is, from the point of view of maximum conversion tothe desired VII, that conversion to the 1α-hydroxy-cis-vitamin structurebe done when the protection of the 3β-hydroxyl is still intact.Paralleling processes 5 and 6 compound X may be converted to VIII andcompound XI to IX, but this is less preferred because of the difficultyof separation at the A-ring dihydroxy stage.

Compounds of formula II thru VII wherein R₂ is the group ##STR7##wherein R₃ is selected from the group consisting of acetoxy andtrimethylsilyloxy and R₄ is hydrogen.

The following examples illustrate the inventive scope. They are intendedto be illustrative of and not limitative of the invention.

Preparation 1: 19-Phenylseleneno 9,10-secocholesta-1(10), 5 E,7E-triene-3β-ol, 3-benzoate

To a solution of cholecalciferol benzoate (20 g) in drydimethylformamide (150 ml) at 65° C., and in an atmosphere of argon, isadded N-phenylseleno succinimide (20 g) and azo-bis-isobutyronitrite(0.5 g), and th mixture maintained at this temperaure for 4 hours. Themixture is poured into water, extracted with hexane (500 ml) and theextracts washed with a solution of sodium bicarbonate and then brine.After drying over sodium sulfate the extracts are evaporated to yield aresidue which is crystallized from a mixture of acetone and methanol toyield 19-phenylseleneno 9,10-sechocholesta-1(10), 5, 7E-triene-3β-ol.3-benzoate, m.p. 211°.

[α]_(D) (CHCl₃ C=0.876)=+212°

Analysis, Calc'd for C₄₀ H₅₂ O₂ Se: C, 74.62; H, 8.14. Found: C, 74.96,H, 7.95%.

NMR (DCDl₃)-δ0.52s (3H); 3.78s (2H); 5.23m(1H); 5.53m (1H); 5.90 and6.62 AB, J=12 Hz, (2H); 7.07-7.63m (8H); 7.90-8.13m (2H).

Utilizing a procedure similar to that described in Preparation 1, butsubstituting the appropriately substituted cholecalciferol forcholecalciferol benzoate there is obtained the following compounds.

                  TABLE 1                                                         ______________________________________                                         ##STR8##                                                                     R.sub.1     R.sub.2              Ar                                           ______________________________________                                        benzoyl                                                                                   ##STR9##             phenyl                                       2-methylbenzoyl                                                                          "                     phenyl                                       3-t-butylbenzoyl                                                                         "                     phenyl                                       4-pentylbenzoyl                                                                          "                     phenyl                                       2-methoxybenzoyl                                                                         "                     phenyl                                       4-pentoxybenzoyl                                                                         "                     phenyl                                       2-chlorobenzoyl                                                                          "                     phenyl                                       3-bromobenzoyl                                                                           "                     phenyl                                       3-fluorobenzoyl                                                                          "                     phenyl                                       4-iodobenzoyl                                                                            "                     phenyl                                       4-nitrobenzoyl                                                                           "                     phenyl                                       2-cyanobenzoyl                                                                            ##STR10##            phenyl                                       acetyl     "                     phenyl                                       propionyl  "                     phenyl                                       butyryl    "                     phenyl                                       pentanoyl  "                     phenyl                                       benzoyl    "                     phenyl                                       2-methylbenzoyl                                                                          "                     phenyl                                       3-ethylbenzoyl                                                                           "                     phenyl                                       4-pentylbenzoyl                                                                          "                     phenyl                                       4-isopropylbenzoyl                                                                       "                     phenyl                                       2-methoxybenzoyl                                                                         "                     phenyl                                       3-propoxybenzoyl                                                                         "                     phenyl                                       4-pentoxybenzoyl                                                                         "                     phenyl                                       2-chlorobenzoyl                                                                          "                     phenyl                                       3-bromobenzoyl                                                                           "                     phenyl                                       2-cyanobenzoyl                                                                            ##STR11##            phenyl                                       acetyl     "                     phenyl                                       propionyl  "                     phenyl                                       butyryl    "                     phenyl                                       pentanoyl  "                     phenyl                                       benzoyl    "                     phenyl                                       2-methbenzoyl                                                                            "                     phenyl                                       3-ethylbenzoyl                                                                           "                     phenyl                                       4-pentylbenzoyl                                                                          "                     phenyl                                       4-isopropylbenzoyl                                                                       "                     phenyl                                       2-methoxybenzoyl                                                                         "                     phenyl                                       3-propoxybenzoyl                                                                         "                     phenyl                                       4-pentoxybenzoyl                                                                         "                     phenyl                                       2-chlorobenzoyl                                                                          "                     phenyl                                       3-bromobenzoyl                                                                           "                     phenyl                                       2-cyanobenzoyl                                                                            ##STR12##            phenyl                                       acetyl     "                     phenyl                                       proprionyl "                     phenyl                                       butyryl    "                     phenyl                                       pentanoyl  "                     phenyl                                       benzoyl    "                     phenyl                                       2-methylbenzoyl                                                                          "                     phenyl                                       3-ethylbenzoyl                                                                           "                     phenyl                                       4-pentylbenzoyl                                                                          "                     phenyl                                       4-isopropylbenzoyl                                                                       "                     phenyl                                       2-methoxybenzoyl                                                                         "                     phenyl                                       3-propoxybenzoyl                                                                         "                     phenyl                                       4-pentoxybenzoyl                                                                         "                     phenyl                                       2-chlorobenzoyl                                                                          "                     phenyl                                       3-bromobenzoyl                                                                           "                     phenyl                                       3-fluorobenzoyl                                                                          "                     phenyl                                       4-iodobenzoyl                                                                            "                     phenyl                                       2-nitrobenzoyl                                                                           "                     phenyl                                       2-cyanobenzoyl                                                                           "                     phenyl                                       benzoyl                                                                                   ##STR13##            phenyl                                       benzoyl                                                                                   ##STR14##            phenyl                                       benzoyl                                                                                   ##STR15##            phenyl                                       benzoyl                                                                                   ##STR16##            phenyl                                       benzoyl                                                                                   ##STR17##            phenyl                                       benzoyl                                                                                   ##STR18##            phenyl                                       benzoyl                                                                                   ##STR19##            phenyl                                       benzoyl                                                                                   ##STR20##            phenyl                                       benzoyl                                                                                   ##STR21##            phenyl                                       benzoyl                                                                                   ##STR22##            phenyl                                       benzoyl                                                                                   ##STR23##            phenyl                                       benzoyl                                                                                   ##STR24##            phenyl                                       benzoyl                                                                                   ##STR25##            phenyl                                       benzoyl                                                                                   ##STR26##            phenyl                                       benzoyl                                                                                   ##STR27##            phenyl                                       benzoyl                                                                                   ##STR28##            phenyl                                       benzoyl                                                                                   ##STR29##            phenyl                                       benzoyl                                                                                   ##STR30##            phenyl                                       benzoyl                                                                                   ##STR31##            phenyl                                       benzoyl                                                                                   ##STR32##            phenyl                                       benzoyl                                                                                   ##STR33##            phenyl                                       benzoyl                                                                                   ##STR34##            phenyl                                       benzoyl                                                                                   ##STR35##            phenyl                                       benzoyl                                                                                   ##STR36##            phenyl                                       benzoyl                                                                                   ##STR37##            phenyl                                       benzoyl                                                                                   ##STR38##            phenyl                                       benzoyl                                                                                   ##STR39##            phenyl                                       benzoyl                                                                                   ##STR40##            phenyl                                       benzoyl                                                                                   ##STR41##            phenyl                                       benzoyl                                                                                   ##STR42##            phenyl                                       benzoyl                                                                                   ##STR43##            phenyl                                       benzoyl                                                                                   ##STR44##            phenyl                                       benzoyl                                                                                   ##STR45##            phenyl                                       benzoyl                                                                                   ##STR46##            phenyl                                       benzoyl                                                                                   ##STR47##            phenyl                                       benzoyl                                                                                   ##STR48##            phenyl                                       benzoyl                                                                                   ##STR49##            phenyl                                       benzoyl                                                                                   ##STR50##            phenyl                                       benzoyl                                                                                   ##STR51##            phenyl                                       benzoyl                                                                                   ##STR52##            phenyl                                       benzoyl                                                                                   ##STR53##            phenyl                                       benzoyl                                                                                   ##STR54##            phenyl                                       benzoyl                                                                                   ##STR55##            phenyl                                       benzoyl                                                                                   ##STR56##            phenyl                                       benzoyl                                                                                   ##STR57##            phenyl                                       benzoyl                                                                                   ##STR58##            phenyl                                       benzoyl                                                                                   ##STR59##            phenyl                                       4-chlorophenyl                                                                            ##STR60##            phenyl                                       2-methylphenyl                                                                            ##STR61##            phenyl                                       3-ethoxyphenyl                                                                            ##STR62##            phenyl                                       4-nitrophenyl                                                                             ##STR63##            phenyl                                       2-bromophenyl                                                                             ##STR64##            phenyl                                       trimethylsilyl                                                                            ##STR65##            phenyl                                       t-butyldimethylsilyl                                                                      ##STR66##            phenyl                                       phenyldimethylsilyl                                                                       ##STR67##            phenyl                                       trimethylsilyl                                                                            ##STR68##            phenyl                                       trimethylsilyl                                                                            ##STR69##            phenyl                                       ______________________________________                                    

Preparation 2: 19-Phenylseleneno 9.10-secocholesta-1(10) 5E,7E-triene-3β-ol. 3 benzoate

To a solution of cholecalciferol benzoate (250 mg) in chloroform (5 ml)is added phenylseleninic anhydride (250 mg) and lithium chloride (20 mg)and heated at 55° for 20 minutes. The solution is poured into water andthe mixture extracted with more chloroform. The extracts are washed witha sodium bicarbonate solution and then brine. After drying, the solutionis evaporated to yield a residue which is chromatographed on silica gel(10% water), eluting with hexane/ethylacetate mixture to yield19-phenylseleno 9,10-secocholesta -1(10) 5E, 7E-triene-3β-ol, 3benzoate.

Preparation 3: 19-Phenylseleneno-9,10 secocholesta-1(10) 5E, 7Etriene-3β-25 diol, 3,25-bis-trimethyl silyl ether

To a solution of 25-hydroxy cholecalciferol-bistrimethylsilyl ether (100mg), prepared in conventional manner from the diol andpyridine/chlorotrimethyl silane, in dry tetrahydrofuran at -78° C., isadded dropwise during a period of 5 minutes to a solution of phenylseenenylchloride (74 mg) in tetrahydrofuran (1 ml). After 20 minutes,1,5-diazabicyclo[4.5.0]undec-5-ene (0.3 ml) is added and the solutionwarmed to room temperature. The mixture is poured into water andextracted with hexane. The extracts are washed successively with brine,dilute hydrochloric acid, brine, a sodium bicarbonate solution and thendried over sodium sulfate. The residue, after evaporation, ischromatographed over silica gel, eluting with hexane containing 1/2%ethyl acetate to yield the crude 19-phenylseleno-9,10secocholesta-1(10)(5E), 7E-triene-3β-25 diol, 3.25 bis-trimethylsilylether as an oil.

NMR (CDCl₃) SO.135(18H); 0.58s (3H); 1.20s (6H); 3.55s (24); 3.55m(1H);5.33m(1H); 5.92 and 6 53 Aβ. J=12 Hz, (2H); F.10-7.60m(5H).

Preparation 4: 19-Phenylseleneno-9,10-secocholesta-1(10), 5E,7E-triene-3β,25-diol, 3-benzoate, 25-trimethyl silylether

(i) To a solution of 25-hydroxycholecalciferol (5.0 g.) in pyridine (25ml.) at -15°, under an atmosphere of argon, is added4-(N,N-dimethylamino)-pyridine (50 mg) followed by benzoyl chloride(2.10 ml.). The solution is warmed to 0° and kept at this temperaturefor 1.5 hours. After cooling to -15°, trimethylcholosilane (1.75 ml.) isadded and then the mixture is heated to room temperature for 10 minutes,before pouring into water. The mixture is extracted with hexane (500ml.) and the extracts washed with brine, dilute hydrochloric acid,brine, sodium bicarbonate solution, brine and then dried over sodiumsulfate. Evaporation of the solution yields 25-hydroxycholecalciferol,3-benzoate, trimethylsilylether as an oil.

(ii) The 25-hydroxycholecalciferol, 3-benzoate, trimethylsilyletherobtained in (i) is dissolved in hexamethyl phosphoric triamide (25 ml.)under an atmosphere of argon and N-phenylselenenosuccinimide (9.0 g.) isadded, and the solution then heated to 72° for 3.5 hours before pouringinto water and extracting with a mixture of methylene chloride (100 ml.)and hexane (200 ml.). The extract is washed successively with water (3times), sodium bicarbonate solution and finally with water. After dryingover sodium sulfate the solution is evaporated to an oil,chromatographed on silica gel (10% water) eluting with ethylacetate/hexane. The product is then crystallized from iso-propanol togive 19-phenylseleneno-9,10-secocholesta-1(10), 5Z,7E-triene-3β.25-diol, 3-benzoate, 25-trimethylsilylether: 0.6 (5ethylacetate in Skellysolve B).

[α]_(D) (CHCl₃, 0=0.8635)+164°.

NMR (CDCl₃): δ0.1s (9H); 0.53s (3H); 0.93d, J=6 Hz (3H); 1.20s (6H);3.80s (2H); 5.27m (1H); 5.53t, J=3 Hz (1H); AB at 5.93 and 6.67, J=11 Hz(2H); 7.17-7.67 complex (8H); 7.80-8.17 complex (2H).

Preparation 4a: Trimethylsilylation of19-phenylseleneno-9,10-secocholesta-1(10),5E,7E-triene-3β, 25-diol,3-benzoate

Trimethylcholosilane (0.10 ml.) is added to a solution of19-phenylseleneno-9,10-secocholesta-1(10),5E,7E-triene-3β-25-diol, 3benzoate (330 mg.) in pyridine (2 ml.) containing4-(N,N-dimethylamino)pyridine (10 mg.) at -15°. After stirring at roomtemperature for 0.5 hour the mixture is poured into water and extractedwith hexane (150 ml.). The extract is washed with dilute hydrochloricacid, brine, sodium bicarbonate solution, and then brine. After dryingover sodium sulfate the solvent is removed and the residue crystallizedfrom isopropanol to give 19-phenylseleneno-9,10-secocholesta-1(10),5E,7E-triene-3β,25-diol, 3-benzoate, 25-trimethylsilylether.

Preparation 5: 19-Phenylseleneno-9,10-secocholesta-1(10),

5E,7E-triene-3β,25-diol, 3-benzoate

A solution of N-phenylselenensuccinimide (9.0 g.) and25-hydroxycholecalciferol-3-benzoate (6.5 g.) is heated at 72° for 4.5hours and then poured into water. The mixture is extracted with a 30%solution of methylenechloride in hexane (500 ml.) and the extractswashed twice with water, sodium bicarbonate solution, water and thendried over sodium sulfate. After removal of solvent the residue ischromatographed on silica gel (10% water) eluting with ethylacetate/hexane (gradient-wise to ca. 7% ethylacetate. The product iscrystallized from isopropanol to give19-phenylseleneno-9,10-secocholesta-1(10), 5E,7E-triene-3β,25β-diol.3-benzoate (2.2 g., 222). Rf: 0.6 (two passes in 20%ethylacetate/Skellysolve B; m.p. 107°-108° C.

[α]_(D) (CHCl₃, C=0.7635)+187°

NMR (CDCl₃): δ0.52s (3H); 0.93d, J=6 Hz (3H); 1.20s (6H); 5.23m (1H);5.53t, J=3 Hz (1H); AB at 5.60 and 6.60, J=11 Hz (2H); 7.17-7.63 complex(8H); 7.93-8.10 complex (2H).

EXAMPLE 1 (i) 9,10-Secocholesta-5Z,7E,10(19)-triene-1α,3β-diol,3-benzoate (ii) 9,10-Secocholesta-5E,7E,10(19)-triene-1β,3β-diol,3-benzoate (iii) 9,10-Secocholesta-5E,7E,10(19)-triene-1α, 3β-diol,3-benzoate

To a stirred solution of 19-phenylseleneno9,10-secocholesta-1(10),5Z,7E-triene-3β-ol, 3-benzoate (1.93 g) in drytetrahydrofuran (20 ml.) containing diisopropylethylamine (0.05 ml) at-16° C. is added 90% hydrogen peroxide (0.25 ml.). The mixture isallowed to warm slowly and at ca -5° C. an exotherm to ca ⁺ 10°occurred. The mixture is poured into water and extracted with ethylacetate. The extracts are washed with dilute hydrochloric acid, brine,sodium bicarbonate solution and then brine. The extracts are dried oversodium sulfate and then evaporated to a residue which waschromatographed on silica gel (10% water) eluting withhexane/ethylacetate mixture. Three compounds are isolated. They are inorder of elution. They are in order of elution:

(i) 9,10-Secocholesta-5Z,7E,10(19)-triene-1α,3β-diol, 3-benzoate.

NMR (CDCl₃): δ0.55s (3H); 4.48m (1H); 5.07s (1H); 5.40s (1H); 5.47m(1H); 6.05 and 6.38 AB. J=11.0 Hz, (2H); 7.27-7.60m (3H): 7.90-8.10m(2H).

Hydrolysis of this material with aqueous methanolic potassium hydroxideyielded crystalline 1α-hydroxycholecalciferol, identical to authenticmaterial.

(ii) 9,10-Secocholesta-5E,7E,10(19)-triene-1β,3β-diol, 3-benzoate.

NMR (CDCl₃): δ0.47s(3H); 4.22m(1H); 5.08s(1H); 5.13s(1H); 5.13m(1H);5.83 and 6.63 AB, J=12H₃, (2H); 7.27-7.60m(3H); 7.90-8.10m(2H).

(iii) 9,10-Secocholesta-5E,7E,10(19)-triene-1α,3β-diol-3-benzoate.

NMR (CDCl₃): 0.40s(3H); 4.57t, J 5 Hz, (1H); 5.03s(1H); 5.15s(1H);5.50m(1H); 5.82 and 6.62 AB, J 12 Hz.(2H); 7.27-7.60m(3H); 7.90-8.10m(2H).

Utilizing procedures similar to those described in Example 1, butsubstituting the appropriate seleneno compounds for19-phenylseleno-9,10-secocholesta-1(10),5Z,7E-triene-3β-ol, 3-benzoatethere is obtained the following compounds

                  TABLE II                                                        ______________________________________                                         ##STR70##                                                                    R.sub.1       R.sub.2                                                         ______________________________________                                        benzoyl                                                                                      ##STR71##                                                      2-methylbenzoyl                                                                             "                                                               3-t-butylbenzoyl                                                                            "                                                               4-pentylbenzoyl                                                                             "                                                               2-methoxybenzoyl                                                                            "                                                               4-pentoxybenzoyl                                                                            "                                                               2-chlorobenzoyl                                                                             "                                                               3-bromobenzoyl                                                                              "                                                               3-fluorobenzoyl                                                                             "                                                               4-iodobenzoyl "                                                               4-nitrobenzoyl                                                                              "                                                               2-cyanobenzoyl                                                                               ##STR72##                                                      acetyl        "                                                               propionyl     "                                                               butyryl       "                                                               pentanoyl     "                                                               benzoyl       "                                                               2-methylbenzoyl                                                                             "                                                               3-ethylbenzoyl                                                                              "                                                               4-pentylbenzoyl                                                                             "                                                               4-isopropylbenzoyl                                                                          "                                                               2-methoxybenzoyl                                                                            "                                                               3-propoxybenzoyl                                                                            "                                                               4-pentoxybenzoyl                                                                            "                                                               2-chlorobenzoyl                                                                             "                                                               3-bromobenzoyl                                                                              "                                                               2-cyanobenzoyl                                                                               ##STR73##                                                      acetyl        "                                                               propionyl     "                                                               butyryl       "                                                               pentanoyl     "                                                               benzoyl       "                                                               2-methbenzoyl "                                                               3-ethylbenzoyl                                                                              "                                                               4-pentylbenzoyl                                                               4-isopropylbenzoyl                                                            2-methoxybenzoyl                                                                            "                                                               3-propoxybenzoyl                                                                            "                                                               4-pentoxybenzoyl                                                                            "                                                               2-chlorobenzoyl                                                                             "                                                               3-bromobenzoyl                                                                              "                                                               2-cyanobenzoyl                                                                               ##STR74##                                                      acetyl        "                                                               propionyl     "                                                               butyryl       "                                                               pentanoyl     "                                                               benzoyl       "                                                               2-methylbenzoyl                                                                             "                                                               3-ethylbenzoyl                                                                              "                                                               4-pentylbenzoyl                                                                             "                                                               4-isopropylbenzoyl                                                                          "                                                               2-methoxybenzoyl                                                                            "                                                               3-propoxybenzoyl                                                                            "                                                               4-pentoxybenzoyl                                                                            "                                                               2-chlorobenzoyl                                                                             "                                                               3-bromobenzoyl                                                                              "                                                               3-fluorobenzoyl                                                                             "                                                               4-iodobenzoyl "                                                               2-nitrobenzoyl                                                                              "                                                               2-cyanobenzoyl                                                                              "                                                               benzoyl                                                                                      ##STR75##                                                      benzoyl                                                                                      ##STR76##                                                      benzoyl                                                                                      ##STR77##                                                      benzoyl                                                                                      ##STR78##                                                      benzoyl                                                                                      ##STR79##                                                      benzoyl                                                                                      ##STR80##                                                      benzoyl                                                                                      ##STR81##                                                      benzoyl                                                                                      ##STR82##                                                      benzoyl                                                                                      ##STR83##                                                      benzoyl                                                                                      ##STR84##                                                      benzoyl                                                                                      ##STR85##                                                      benzoyl                                                                                      ##STR86##                                                      benzoyl                                                                                      ##STR87##                                                      benzoyl                                                                                      ##STR88##                                                      benzoyl                                                                                      ##STR89##                                                      benzoyl                                                                                      ##STR90##                                                      benzoyl                                                                                      ##STR91##                                                      benzoyl                                                                                      ##STR92##                                                      benzoyl                                                                                      ##STR93##                                                      benzoyl                                                                                      ##STR94##                                                      benzoyl                                                                                      ##STR95##                                                      benzoyl                                                                                      ##STR96##                                                      benzoyl                                                                                      ##STR97##                                                      benzoyl                                                                                      ##STR98##                                                      benzoyl                                                                                      ##STR99##                                                      benzoyl                                                                                      ##STR100##                                                     benzoyl                                                                                      ##STR101##                                                     benzoyl                                                                                      ##STR102##                                                     benzoyl                                                                                      ##STR103##                                                     benzoyl                                                                                      ##STR104##                                                     benzoyl                                                                                      ##STR105##                                                     benzoyl                                                                                      ##STR106##                                                     benzoyl                                                                                      ##STR107##                                                     benzoyl                                                                                      ##STR108##                                                     benzoyl                                                                                      ##STR109##                                                     benzoyl                                                                                      ##STR110##                                                     benzoyl                                                                                      ##STR111##                                                     benzoyl                                                                                      ##STR112##                                                     benzoyl                                                                                      ##STR113##                                                     benzoyl                                                                                      ##STR114##                                                     benzoyl                                                                                      ##STR115##                                                     benzoyl                                                                                      ##STR116##                                                     benzoyl                                                                                      ##STR117##                                                     benzoyl                                                                                      ##STR118##                                                     benzoyl                                                                                      ##STR119##                                                     benzoyl                                                                                      ##STR120##                                                     benzoyl                                                                                      ##STR121##                                                     4-chlorophenyl                                                                               ##STR122##                                                     2-methylphenyl                                                                               ##STR123##                                                     3-ethoxyphenyl                                                                               ##STR124##                                                     4-nitrophenyl                                                                                ##STR125##                                                     2-bromophenyl                                                                                ##STR126##                                                     trimethylsilyl                                                                               ##STR127##                                                     t-butyldimethylsilyl                                                                         ##STR128##                                                     phenyldimethylsilyl                                                                          ##STR129##                                                     trimethylsilyl                                                                               ##STR130##                                                     trimethylsilyl                                                                               ##STR131##                                                     ______________________________________                                    

EXAMPLE 2:9,10-Secocholesta-5E,7E,10(19)-triene-1α,3β,25-triol-3.25-bis-trimethylsilylether

In a manner similar to that described in Example 1(iii),19-phenylseleneno-9,10-secocholesta-1(10),5E,7E-triene-3β,25-diol,3,25-bistrimethylsilylether is oxidized to yield9,10-secocholesta-5E,7E,10(19)-triene-1α,3β,25-triol-3,25-bistrimethylsilylether.

NMR (CDCl₃): δ0.15s(9H); 0.20s(9H); 0.61s(3H); 125s(6H); 4.20m(1H);4.50m(1H); 4.98s(1H); 5.11s(1H); 5.88 and 6.58 AB, J=12 Hz, (2H).

Hydrolysis with dilute hydrochloric yielded crystalline9,10,secocholesta-5E,7E,10(19)-triene-1α,3β,25-triol.

NMR (CDCl₃): δ0.59s(3H); 0.72s(6H); 4.19m(1H); 4.49m(1H); 4.87s(1H);5.12s(1H); 5.87 and 6.57AB, J=12H₂, (2H).

Utilizing the procedure similar to that used in Example 2, butsubstituting the 3,25-substituted phenylseleneno compounds described inPreparation 1 for 19-phenylseleneno-9,10-secocholesta-1(10),5E,7E-triene-3β,25-diol,3,25-bistrimethylsilylether there is obtained the corresponding9,10-secocholesta-5E,7E,10(19)-triene-1α,3β,25-triol, 3,25-derivative.

EXAMPLE 3: 9,10-Secocholesta-5Z,7E,10(19)-triene-1α,3β-diol, 3-benzoate

9,10-Secocholesta-5E,7E,10(19)-triene-1α,3β-diol, 3-benzoate (100 mg.)is dissolved in hexane (20 ml.) in a pyrex photo reaction tube and thesolution vigorously deoxygenated, the atmosphere above the solutionbeing replaced by argon. The solution is irradiated with 253.7 n.m.lamps for three hours. The solution is then placed directly on a silicagel (10% water) chromatographic column and the product9,10-secocholesta-5Z,7E,10(19)-triene-1α,3β-diol, 3-benzoate separatedfrom the residual starting material.

The product has:

NMR (CDCl₃): 0.55s(3H); 4.48m(1H); 5.07s(1H); 5.40s(1H); 5.47m(1H); 6.05and 6.38, AB, J=11.0 Hz,(2H); 7.27-7.60m(3H); 7.90-8.10m(2H).

This material is identical to the product (i) in Example 1. Hydrolysisof this material with aqueous methanolic potassium hydroxide yields9,10-secocholesta-5Z,7E,10(19)-triene 1α,3β-diol that is identical withan authentic sample.

EXAMPLE 4: 9,10-Secocholesta-5Z,7E,10(19)-triene-1α,3β,25-triol,3,25-Bis-trimethylsilylether

In a like fashion to that described in Example 3,9,10-secocholesta-5E,7E,10(19)-triene-1α,3β,25-triol-3,25-bis-trimethylsilylderivative is irradiated to yield9,10-secocholesta-5Z,7E,10(19)-triene-1α,3β,25-triol,3,25-bis-trimethylsilyl derivative.

NMR (CDCl₃): δ0.16s(9H); 0.20s(9H); 0.61s(3H); 1.25s(6H); 4.23m(1H);4.45m(1H); 5.00s(1H); 5.30s(1H); 6.03 and 6.40 AB, J=11.5 Hz, (2H).

Mild hydrolysis with cold dilute hydrochloric acid yields9,10-secocholesta-5Z,7E,10(19)-triene-1α,3β,25-triol identical to anauthentic specimen.

EXAMPLE 5: 9,10-Secocholesta-5Z,7E,10(19)-triene-1β,3β-diol, 3-benzoate

In a similar fashion to that described in Example 3,9,10-secocholesta-5E,7E,10(19)-triene-1β,3β-diol-3-benzoate isirradiated to yield 9,10-secocholesta-5Z,7E,10(19)-triene-1β,3β-diol,3-benzoate.

NMR (CDCl₃): δ0.52s(3H); 4.20m(1H); 5.03s(1H); 5.17m(1H); 5.40m(1H);6.00 and 6.42 AB, J=11.05, (2H); 7.27-7.60m(3H); 7.90-8.10m(2H).

Hydrolysis of this material with aqueous methanolic potassium hydroxideyields 9,10-secocholesta-5Z,7E,10(19)-triene-1β,3β,diol.

NMR (CDCl₃): δ0.53s(3H); 4.07m(1H); 4.33m(1H); 4.98(1H); 5.27s(1H); 6.05and 6.43 AB, J=10.5 Hz, (2H).

EXAMPLE 6: Oxidation of19-phenylseleneno-9,10-secocholesta-1(10),5E,7E-triene-3β-25-diol,3-benzoate,25-trimethylsilylether

To a solution of19-phenylseleneno-9,10-secocholesta-1(10),5Z,7E-triene-3β,25-diol,3-benzoate, 25-trimethylsilylether (2.40 g.) in dry tetrahydrofuran (25ml.) containing diiso-propylethylamine (0.05 ml.) under argon at -15° isadded dropwise a solution of diphenyldiselenide (50 mg.) anddiisopropylethylamine (0.05 ml.) in dry tetrahydrofuran (5 ml.) that hasbeen heated with hydrogen peroxide (0.20 ml., 90%) at 50° until it isclear and colorless. The solution is allowed to warm slowly to -10° atwhich temperature a pronounced exotherm is observed. The mixture ispoured into cold water and extracted with methylene chloride (500 ml.).The extract is washed with cold dilute hydrochloric acid, cold brine,cold sodium bicarbonate solution, cold brine and then dried over sodiumsulfate. The solvent is removed and the oily residue chromatographedover silica gel (10% water) eluting with ethyl acetate/Skellysolve Bgradient wise. The products elutes at ca. 8-9% ethyl acetate. The firstmaterial eluted is 9,10-secocholesta-5E,7E,10(19)-triene-1β,3β,25-triol,3-benzoate, 25-trimethylsilylether.

Rf: 0.45 (20% ethylacetate/Skellysolve B).

The second material eluted is9,10-secocholesta-5E,7E,10(19)-triene-1α,3β,25-triol, 3-benzoate,25-trimethylsilylether.

NMR (CDCl₃): δ0.1s(9H); 0.40s(3H); 0.90d, J=6 Hz(3H); 5.03s(1H);5.13(1H); 5.50m(1H); AB at 5.80 and 6.60, J=11 Hz (2H); 7.17-7.60complex (3H); 7.90-8.10 complex (2H).

EXAMPLE 7: 9,10-Secocholesta-5Z,7E,10(19)-triene-1α,3β,25-triol,3-benzoate, 25-trimethylsilylether

9,10-Secocholesta-5E,7E,10(19)-triene-1α,3β-25-triol, 3-benzoate,25-trimethylsilylether (52 mg.). is dissolved in dry tetrahydrofuran (20ml.) in a pyrex photoreaction tube, and the solution rigorouslydeoxygenated. The atmosphere above the solution is replaced with argon.The solution is irradiated with 253.7 n.m. lamps for four hours. Thesolvent is removed and the residue chromatographed on silica gel (10%water) eluting with ethyl acetate/hexane. The product,9,10-secocholesta-5Z,7E,10(19)-triene-1α,3β-25-triol, 3-benzoate,25-trimethylsilylether (52 mg.), is eluted first, followed by residualstarting material (both being eluted with ca. 8-9% ethylacetate). Theproduct has

NMR (CDCl₃): δ0.1s(9H); 0.6s(3H); 0.93d, J=6 Hz (3H); 1.20s(6H);4.50M(1H); 5.07s(1H); 5.40s(1H); 5.47m(1H); AB at 6.05 and 6.38, J=11 Hz(2H); 7.17-7.60 complex (3H); 7.90-8.10 complex (2H).

EXAMPLE 8: 1α-25-Dihydroxycholecalciferol

To a solution of 9,10-secocholesta-5Z,7E,10(19)-triene-1α,3β,25-triol,3-benzoate, 25-trimethylsilylether (350 mg.) in tetrahydrofuran (2 ml.)and methanol (2 ml.) is added dilute hydrochloric acid (0.5 ml., 0.5N).After 1 minute this is followed by a solution of sodium hydroxide (0.1ml., 50%). The mixture is heated at 45° for 0.5 hour and then pouredinto brine. The mixture is extracted with a 5% solution of methanol inmethylene chloride (150 ml.). The extracts are washed twice with brineand then dried over sodium sulfate. The solvent is removed and theresidue crystallized from methylene chloride (3 ml.) to give1α,25-dihydroxycholecalciferol, identical with an authentic samplebenzoate as an oil.

Rf: 0.65 (20% ethyl acetate/Skellysolve B).

EXAMPLE 9: 9,10-Secocholesta-5E,7E,10(19)-triene-1β,3β,25-triol,3-benzoate and 9,10-secocholesta-5E,7E-10(19)-triene-1α,3β,25-triol,3-benzoate

In a manner exactly similar to that described in Example 6,19-phenylseleneno-9,10-secocholesta-1(11),5E, 7E-triene-3β, 25-diol,3-benzoate (2.25 g.) is oxidized to mixture of the 1α- and1β-hydroxy-trans-vitamin derivatives, which are separated bychromatography on silica gel (10% water) eluting with ethylacetate/hexane, gradient-wise to ca. 20% ethyl acetate.

The 9,10-secocholesta-5E,7E,10(19)-triene-1β,3β, 25-triol, 3-benzoate iseluted first.

Rf=0.4 (40% ethyl acetate/Skellysolve B). The9,10-secocholesta-5E,7E,10(19)-triene-1α,3β,25-triol, 3-benzoate iseluted next.

Rf: 0.35 (40% ethyl acetate/Skellysolve B).

NMR (CDCl₃): δ0.40s(3H); 0.90d, J=6 Hz (3H); 1.20s(6H); 4.53t, J=3 Hz(1H); 5.03s(1H); 5.13s(1H); 5.50m(1H); AB at 5.80 and 6.60, J=11 Hz(2H); 7.17-7.50 complex (3H); 7.90-8.10 complex (2H).

I claim:
 1. A compound selected from the group consisting of compoundshaving the formula ##STR132## wherein R₁ is selected from the groupconsisting of hydrogen, trimethylsilyl, t-butyldimethylsilyl,phenyldimethylsilyl, acyl of from 2 to 6 carbon atoms, and aroyl whereinthe aryl group is phenyl or substituted by a lower alkyl, lower alkoxy,halogen, nitro or a cyano group; R₂ is selected from the groupconsisting of ##STR133## wherein R₃ is selected from the groupconsisting of hydrogen, hydroxy, trimethylsilyloxy, acyloxy of from 2 to6 carbon atoms, inclusive and aryloxy; R₄ is selected from the groupconsisting of hydrogen, hydroxy, trimethylsilyloxy,t-butyldimethylsilyloxy, phenyldimethylsilyloxy, acyloxy of from 2 to 6carbon atoms, inclusive, benzoyl, substituted benzoyl; and wherein R₃and R₄ when taken together form a group selected from the groupconsisting of acetonide, carbonate and thiocarbonate; ##STR134## whereinR₅ is selected from the group consisting of hydrogen, methyl hydroxyland lower alkoxyl of from 1 to 5 carbon atoms, inclusive; with theproviso that when R₂ is the group ##STR135## and R₃ is hydrogen orhydroxy R₁ cannot be hydrogen or acyloxy.
 2. Compounds according toclaim 1 wherein R₂ is selected from the group consisting ##STR136##wherein R₁, R₃ and R₄ are the same as in claim
 1. 3. Compounds of claim2 having the formula ##STR137## wherein R₁ and R₃ are the same as inclaim 2, wherein R₁ is selected from the group consisting of hydroge,trimethylsilyl, t-butyldimethylsilyl, phenyldimethylsilyl, acyl of from2 to 6 carbon atoms, and aroyl; R₃ is selected from the group consistingof hydrogen, hydroxy, trimethylsilyloxy, acyloxy of from 2 to 6 carbonatoms, inclusive, and aroyloxy.
 4. A compound according to claim 3wherein R₁ is selected from the group consisting of trimethylsilyl andaroyl and R₃ is selected from the group consisting of hydrogen, hydroxy,trimethylsilyloxy and acyl of from 2 to 6 carbon atoms, inclusive.
 5. Acompound according to claim 4 wherein R₁ is benzoate and R₃ is hydrogenso that the specific embodiment is9,10-secocholesta-5Z,7E,10(19)-triene-1α,3β-diol, 3-benzoate.
 6. Acompound according to claim 4 wherein R₁ is trimethylsilyl and R₃ istrimethylsilyloxy so that the specific embodiment is9,10-secocholesta-5Z,7E,10(19)-triene-1α,3β,25-triol,3,25-bis-trimethylsilylether.
 7. A compound according to claim 4 whereinR₁ is benzoate and R₃ is trimethylsilyloxy so that the specificembodiment is 9,10-secocholesta-5Z,7E,10(19)-triene-1α,3β-25-triol,3-benzoate, 25-trimethylsilylether.
 8. A compound according to claim 4wherein R₁ is benzoate and R₃ is hydroxy so that the specific embodimentis 9,10-secocholesta-5Z,7E,10(19)-triene-1α,3β-25-triol, 3-benzoate. 9.A compound according to claim 4 wherein R₁ is benzoate and R₃ is acetoxyso that the specific embodiment is9,10-secocholesta-5Z,7E,10(19)-triene-1α,3β-25-triol, 3-benzoate,25-acetate.
 10. Compounds of claim 2 having the formula ##STR138##wherein R₁ is selected from the group consisting of hydrogen,trimethylsilyl, t-butyldimethylsilyl, phenyldimethylsilyl, acyl of from2 to 6 carbon atoms, and aroyl wherein the aryl group is phenyl orphenyl substituted by a lower alkyl, lower alkoxy, halogen, nitro or acyano group; R₃ is selected from the group consisting of hydrogen,hydroxy, trimethylsilyloxy, acyloxy of from 2 to 6 carbon atoms,inclusive, and aroyloxy.
 11. A compound according to claim 10 wherein R₁is selected from the group consisting of trimethylsilyl and aroyl and R₃is selected from the group consisting of hydrogen, hydroxy,trimethylsilyloxy and acyloxy of from 2 to 6 carbon atoms, inclusive.12. A compound according to claim 11 wherein R₁ is benzoate and R₃ ishydrogen so that the specific embodiment is9,10-secocholesta-5E,7E,10(19)-triene-1α,3β-diol, 3-benzoate.
 13. Acompound according to claim 11 wherein R₁ is hydrogen and R₃ is hydroxyso that the specific embodiment is9,10-secocholesta-5E,7E,10(19)-triene-1α,3β,25-triol.
 14. A compoundaccording to claim 11 wherein R₁ is trimethylsilyl and R₃ istrimethylsilyloxy so that the specific embodiment is9,10-secocholesta-5E,7E,10(19)-triene-1α,3β,25-triol-3,25-bis-trimethylsilylether.15. A compound according to claim 11 wherein R₁ is benzoate and R₃ istrimethylsilyloxy so that the specific embodiment is9,10-secocholesta-5E,7E,10(19)-triene-1α,3β,25-triol, 3-benzoate,25-trimethylsilylether.
 16. A compound according to claim 11 wherein R₁is benzoate and R₃ is hydroxy so that the specific embodiment is9,10-secocholesta-5E,7E,10(19)-triene-1α,3β,25-triol, 3-benzoate.
 17. Acompound according to claim 11 wherein R₁ is benzoate and R₃ is acetoxyso that the specific embodiment is9,10-secocholesta-5E,7E,10(19)-triene-1α,3β-25-triol, 3-benzoate,25-acetate.
 18. A compound of claim 2 having the formula ##STR139##wherein R₁ is selected from the group consisting of hydrogen,trimethylsilyl, t-butyldimethylsilyl, phenyldimethylsilyl, acyl of from2 to 6 carbon atoms, and aroyl wherein the aryl group is phenyl orphenyl substituted by a lower alkyl, lower alkoxy, halogen, nitro or acyano group; R₃ is selected from the group consisting of hydrogen,hydroxy, trimethylsilyloxy, acyloxy of from 2 to 6 carbon atoms,inclusive, and aroyloxy.
 19. A compound according to claim 18 wherein R₁is selected from the group consisting of trimethylsilyloxy and aroyl andR₃ is selected from the group consisting of hydrogen, hydroxy,trimethylsilyloxy and acyloxy of from 2 to 6 carbon atoms, inclusive.20. A compound according to claim 19 wherein R₁ is benzoate and R₃ ishydrogen so that the specific embodiment is9,10-secocholesta-5Z,7E,10(19)-triene-1β,3β-diol, 3-benzoate.
 21. Acompound of claim 2 having the formula ##STR140## wherein R₁ is selectedfrom the group consisting of hydrogen, trimethylsilyl,t-butyldimethylsilyl, phenyldimethylsilyl, acyl of from 2 to 6 carbonatoms, and aroyl wherein the aryl group is phenyl or phenyl substitutedby a lower alkyl, lower alkoxy, halogen, nitro or cyano group; R₃ isselected from the group consisting of hydrogen, hydroxy,trimethylsilyloxy, acyloxy of from 2 to 6 carbon atoms, inclusive, andaroyloxy.
 22. A compound according to claim 21 wherein R₁ is selectedfrom the group consisting of trimethylsilyl and aroyl and R₃ is selectedfrom the group consisting of hydrogen, hydroxy, trimethylsilyloxy andacyl of from 2 to 6 carbon atoms, inclusive.
 23. A compound according toclaim 22 wherein R₁ is benzoyl and R₃ is hydrogen so that the specificembodiment is 9,10-secocholesta-5E,7E,10(19)-triene-1β,3β-diol,3-benzoate.
 24. A compound according to claim 22 wherein R₁ is benzoyland R₃ is hydroxy so that the specific embodiment is9,10-secocholesta-5E,7E,10(19)-triene-1β,3β,25-triol-3-benzoate.
 25. Acompound according to claim 22 wherein R₁ is benzoyl and R₃ istrimethylsilyloxy so that the specific embodiment is9,10-secocholesta-5E,7E,10(19)-triene-1β,3β-25-triol, 3-benzoate,25-trimethylsilylether.
 26. A compound according to claim 22 wherein R₁is benzoyl and R₃ is acetoxy so that the specific embodiment is9,10-secocholesta-5E,7E,10(19)-triene-1β,3β-25-triol, 3-benzoate,25-acetate.
 27. A compound according to claim 11 wherein R₁ istertiarybutyldimethylsilyl and R₃ is hydrogen so that the specificembodiment is9,10-secocholesta-5E,7E,10(19)-triene-1α,3β-diol,3-tertiarybutyldimethylsilylether.28. A compound according to claim 22 wherein R₁ istertiarybutyldimethylsilyl and R₃ is hydrogen so that the specificembodiment is 9,10-secocholesta-5E,7E,10(19)-triene-1β,3β-diol,3-tertiarybutyldimethylsilylether.